Despite the magnitude of the medical problem which prostate cancer constitutes, a basic understanding of the molecular events responsible for the initiation and progression of this disease remains elusive. The goal of the proposed research is to identify, localize and characterize consistent alterations in the prostate cancer cell genome. This information is prerequisite for the long term goal of this project which is to identify and clone the genes which, as a result of genetic alteration, are responsible for prostate carcinogenesis. To this end, a systematic approach utilizing molecular and cell biology techniques will be employed to analyze molecular genetic aspects of human prostate cancer. Specifically, three different project areas will be pursued. 1) We will identify and evaluate candidate prostate tumor suppressor genes located at chromosome 8p22. At this location we have identified a one megabase (or smaller) region that has a high probability of containing a novel prostate tumor suppressor gene based upon previous deletion mapping studies. 2) To provide the basis for identification of additional genes involved in prostate cancer genomic hybridization (CGH) to be frequently deleted in advanced prostate cancer, i.e. the long arms of chromosomes 2,5,6 and 13. Similarly, regions shown by CGH to be consistently amplified in advanced prostate cancer (i.e. the short arm of chromosome 7 and the long arms of chromosomes 8,9 and 17) will be delineated by amplicon mapping. Tumors to be analyzed will include localized and metastatic cancers from treated and untreated men as well as PIN lesions and cancers from men with a strong family history of prostate cancer. 3) An assessment of DNA methylation- associated gene suppression will be undertaken to determine the potential role of this non-mutational mechanism of tumor suppression will be undertaken to determine the potential role of this non-mutational mechanism of tumor suppressor gene inactivation in prostate cancer progression. This project will complement other projects in our SPORE program, in particular, the linkage analysis and other studies involving characterization of genetic alterations in prostate cancer. It is anticipated that this multifaceted approach will generate new prognostic markers as well as identify new therapeutic targets in prostate cancer, resulting in an increased ability to effectively diagnose and treat this extremely common malignancy.